Respiratory Dysfunction in 6-OHDA-Induced Parkinson's Disease Rodent (rat) Models

Project Summary Parkinson's Disease (PD) is the second most common neurodegenerative disease, affecting as many as 1 million Americans and ~7-10 million people worldwide. While PD is characterized by motor symptoms of resting tremor, rigidity, bradykinesia, and postural instability, a number of non-motor symptoms (NMS) are also observed. Amongst the NMS, breathing abnormalities have been noted in PD patients since the disease was first described in 1817, and respiratory complications remain the leading cause of death in PD. Respiratory dysfunction in PD manifests as a variety of altered breathing patterns as well as deficits in chemical control of breathing, which may further contribute to PD-related breathing abnormalities. Experimental (animal) models of PD have been developed and implemented in order to gain insight into causes and symptoms of PD as well as the impact of potential therapeutic interventions on ameliorating PD symptoms. One of the common and extensively used approaches involves administration of the neurotoxin 6-hydroxydopamine (6-OHDA) to selectively destroy dopaminergic (DA) neurons when injected directly into the nigrostriatal pathway, specifically into the substantia nigra pars compacta (SNpc), medial forebrain bundle (MFB), or caudate- putamen (CPu). While each site-targeted model has advantages and disadvantages, each seems to capture some, but not all, aspects of the clinical motor and non-motor PD phenotype albeit little is known about the respiratory phenotype in any of these models. Thus, there is a need to develop a better understanding of respiratory abnormalities in these experimental models of PD in order (1) to provide insights into the possible pathological mechanisms responsible for producing and exacerbating respiratory dysfunction in PD and (2) to aid in the development of new and effective therapeutic approaches to ameliorate this common NMS. This R21 application proposes an exploratory/developmental project designed to characterize and quantify the respiratory phenotype in these three commonly used 6-OHDA-induced PD rat models. In specific aim 1, we will evaluate the extent and progression (time course) of respiratory dysfunction in each PD model using serial plethysmography to measure basal ventilatory activity and the responses to acute changes in chemical respiratory drive in conscious spontaneously breathing adult rats. In specific aim 2, we will evaluate the contributions of neural respiratory-related upper airway (genioglossus), pump muscle (diaphragm), and expiratory (external oblique) motor dysfunction in each PD model using acute/terminal electrophysiology experiments to measure basal respiratory-related neural (EMG/ENG) activities and the responses to acute changes in chemical respiratory drive in anesthetized spontaneously breathing adult rats. Thus, this R21 application will (1) identify whether each of the 6-OHDA-lesioned PD rat models is a viable model for studying respiratory abnormalities in PD, (2) provide insight into prospective mechanisms underlying respiratory dysfunction, and (3) provide preliminary data that could serve as the basis of a future R01 application.